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In This Issue:
• Ribavirin Sustains Response to Interferon
• 4-Week Response Predicts Eventual Treatment Outcome
• Immune Response to HCV
• Fibrosis in African Americans and Caucasians with HCV
• Noninvasive Markers of Fibrosis
Ribavirin Sustains Response to Interferon
Ribavirin helps prevent relapse and increases the likelihood of sustained virological response (SVR) to interferon, but its mechanism is not well understood. In the October 2006 issue of Gastroenterology, J.P. Bronowicki and colleagues described a study investigating the role of ribavirin in HCV clearance during therapy and the consequences of ribavirin discontinuation in 516 genotype 1 patients who achieved virological suppression with pegylated interferon plus 800 mg/day ribavirin. At Week 24, 70% of patients had undetectable HCV RNA; this group was randomly assigned to continue combination therapy or stop ribavirin and continue pegylated interferon alone. The 24-week responders who stopped ribavirin had a significantly higher rate of virological breakthrough during the remainder of therapy and relapse after treatment, achieving an SVR rate of 52.8%, compared with 68.2% for patients who continued combination therapy. However, adverse event profiles and quality of life tended to improve in patients who stopped ribavirin. While the researchers concluded that most genotype 1 patients require a full 48-week course of ribavirin, they said that baseline factors could help identify 24-week responders who may be able to stop ribavirin early without losing their chance of achieving sustained response.
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4-Week Response Predicts Eventual Treatment Outcome
Data continues to accumulate that rapid virological response (RVR) early in therapy predicts which patients will go on to achieve sustained response. As reported in the October 2006 Journal of Viral Hepatitis, M. Martinot-Peignoux and colleagues developed a multivariate model to predict SVR or non-response at baseline and during the first 12 weeks of therapy, based on data from 186 chronic hepatitis C patients treated with pegylated interferon plus ribavirin. Variables included were sex, age, prior treatment, HCV genotype, baseline ALT, necroinflammation and fibrosis scores, and HCV RNA at baseline and at weeks 4, 8, and 12. At baseline, the model had a positive predictive value of 95%, which improved to 100% at week 4. Negative predictive value increased from 91% at baseline to 97% at week 4. Based on these results, the researchers suggested that the model could be used to support a 4-week “stopping rule” to decide when to discontinue therapy in patients who are unlikely to achieve sustained response.
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Immune Response to HCV
In recent years, much has been learned about how the immune system fights HCV, but much remains unknown, including the factors that determine who will spontaneously clear the virus and mechanisms underlying treatment response. In the October 1, 2006 Journal of Infectious Diseases, A.I. Romero and colleagues investigated associations between liver histology, viral kinetic response, treatment outcome, and levels of interferon-gamma-inducible protein-10 (IP-10) – a cytokine that appears to play a role in cell proliferation, blood vessel generation, and apoptosis – in 265 chronic hepatitis C patients treated with pegylated interferon plus ribavirin. In a univariate analysis, low baseline plasma IP-10 was significantly associated with low baseline HCV viral load, RVR, SVR, and less pronounced liver fibrosis, inflammation, and steatosis. IP-10 levels decreased six weeks into treatment and remained low in patients who eventually achieved SVR, but rebounded in patients who had persistent detectable HCV RNA after completion of therapy.
In another study, reported in the October 2006 Journal of Viral Hepatitis, A. Ulsenheimer and colleagues assessed the in vitro activity of HCV-specific CD4 helper T-cells from a patient with acute infection using HLA DR4 tetramers. Proliferative responses were initially absent, recovered as HCV viral load decreased, and were lost again during HCV relapse. This pattern of transient CD4 cell proliferative response was observed as HCV was partially controlled by the immune system, and relapse was associated with the emergence of dysfunctional CD4 cell populations. “Failure to control HCV in acute disease may relate to the capacity to sustain efficient immune responses as the virus attempts to ‘bounce back’ after partial control,” the researchers concluded.
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Fibrosis in African Americans and Caucasians with HCV
For reasons that are not fully understood, the natural history of hepatitis C varies among patients of different racial/ethnic groups. As reported in the October 2006 issue of Hepatology, R.J. Fontana and colleagues devised a model incorporating clinical and laboratory parameters to estimate the probability of severe fibrosis in 194 African American and 205 Caucasian untreated genotype 1 patients in the Virahep-C study. The model was then validated in a separate cohort of 461 untreated patients. The distribution of fibrosis scores was similar in Caucasian and African American patients, as was the proportion with severe fibrosis (35% vs 39%). Factors independently associated with severe fibrosis were age, AST and alkaline phosphatase levels, and platelet count. The area under the receiver operating characteristic curve (AUROC) of the Virahep-C model – a measure of predictive performance – was significantly better than that of other models (0.837 in the original cohort and 0.851 in the validation cohort). The researchers concluded that, “A model consisting of widely available clinical and laboratory features predicted severe hepatic fibrosis equally well in African American and Caucasian patients with HCV genotype 1 and was superior to other published models.”
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Noninvasive Markers of Fibrosis
Three studies reported in the October 2006 Journal of Viral Hepatitis assessed various noninvasive methods for assessing fibrosis progression in patients with chronic hepatitis C. M. Bourliere and colleagues assessed 235 patients in the French Fibropaca study, comparing results from FibroTest, AST-to-platelet ratio index (APRI), and Forns index against liver biopsies performed the same day. For the diagnosis of significant fibrosis, the AUROCs for FibroTest, APRI, and Forns index were 0.81, 0.71, and 0.76, respectively; for cirrhosis, the AUROCs for FibroTest and APRI were 0.82 and 0.81, respectively. Using each index independently, all patients were accurately classified using FibroTest, 91% using APRI, and 55% using Forns index. However, there was more discordance between APRI and liver biopsy than between FibroTest or Forns index and biopsy. Performing all three tests allowed accurate assessment of fibrosis without liver biopsy in 81% of patients, but biopsies remained necessary for 19%.
C. Christensen and colleagues evaluated FibroSpect II, a panel of three markers of extracellular matrix remodeling, using 142 serum samples. Using a cut-off of 0.42 (out of 1.0), FibroSpect classified 93% of patients with Ishak fibrosis scores of 3-6 as having advanced fibrosis (Metavir stages F2-F4). Conversely, 66% of patients with Ishak scores of 0-2 were classified as having absent or mild fibrosis (Metavir stages F0-F1). FibroSpect had a positive predictive value of 63%, a negative predictive value of 94%, and an overall accuracy of 76%. “FibroSpect was clinically useful in ruling out advanced fibrosis in hepatitis C by identifying patients with mild disease in whom treatment could be deferred,” the researchers concluded; however, as with other noninvasive tests, the limitation was decreased accuracy in the middle range.
In the third study, C. Trocme and colleagues evaluated a fibrosis index combining serum procollagen type III N-terminal peptide (PIIINP) and matrix metalloproteinase 1 (MMP-1), two markers of extracellular matrix remodeling. The study included 79 patients treated with conventional interferon plus ribavirin for 24 or 48 weeks. The PIIINP/MMP-1 index was significantly correlated with Metavir fibrosis stage. The overall AUROC diagnostic value was 0.77 for discriminating stage F1 vs F2-F4 and 0.81 for discriminating F1/F2 vs F3/F4. PIIINP/MMP-1 index scores decreased significantly starting early in the course of treatment in responders, but remained stable in nonresponders. “Our study shows that a noninvasive index combining PIIINP and MMP-1 is a useful tool to follow-up fibrosis change during and after antiviral therapy chronic hepatitis C patients,” the researchers concluded.
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